Atherosclerosis is a process where deposits of fatty substances, cholesterol and other substances build up in the inner lining of an artery. This buildup is called plaque. Plaques that rupture cause blood clots to form that can block blood flow to the heart (heart attack) or the brain (stroke). Heart attack is the number one cause of death for both men and women in the United States and stroke is the number three cause of death [see, for example, Nature Medicine, Special Focus on Atherosclerosis, (2002) 8:1209-1262]. Abnormally high levels of circulating lipids are a major predisposing factor in development of atherosclerosis. Elevated levels of low density lipoprotein (LDL) cholesterol, elevated levels of triglycerides, or low levels of high density lipoprotein (HDL) cholesterol are, independently, risk factors for atherosclerosis and associated pathologies. In addition, high levels of plasma free fatty acids are associated with insulin resistance and type 2 diabetes.
Diabetes afflicts several million people worldwide. In the United States alone, there are more than 18 million diabetics, with 600,000 new cases diagnosed each year. People with diabetes are at higher risk for heart disease, blindness, kidney failure, infection, extremity amputations, and other chronic conditions. It is estimated that the direct medical expenditures and indirect expenditures attributable to diabetes in the United States were $132 billion in 2002. Taken together, diabetes complications are one of the nation's leading causes of death.
One strategy for decreasing LDL-cholesterol, increasing HDL-cholesterol, and decreasing plasma free fatty acids is to inhibit lipolysis in adipose tissue. This approach involves regulation of hormone sensitive lipase, which is the rate-limiting enzyme in lipolysis. Lipolytic agents increase cellular levels of cAMP, which leads to activation of hormone sensitive lipase within adipocytes. Agents that lower intracellular cAMP levels, by contrast, would be antilipolytic.
It is also worth noting that an increase in cellular levels of cAMP down-regulates the secretion of adiponectin from adipocytes [Delporte, M. L. et al. Biochem J (2002) July]. Reduced levels of plasma adiponectin have been associated with metabolic-related disorders, including atherosclerosis, coronary heart disease, insulin resistance and type 2 diabetes [Matsuda, M. et al. J. Biol. Chem. (2002) July and reviewed therein].
Niacin is also one of the oldest used drugs for the treatment of lipid-associated disorders. It is a valuable drug in that it favorably affects virtually lipid parameters [Goodman and Gilman's Pharmacological Basis of Therapeutics, editors Harmon J G and Limbird L E, Chapter 36, Mahley R W and Bersot T P (2001) pages 971-1002]. Unfortunately, the doses of niacin required to alter serum lipid levels can be quite large and at these dosages adverse side effects are frequent. Side effects can include intense cutaneous flushing, gastrointestinal disturbances, liver toxicity, and disruption of glucose metabolism and uric acid levels. Often, 30-40% of patients cease taking niacin treatment within days after initiating therapy. Statins are also commonly used to treat lipid-associated disorders. The side effects of statins include muscle pain, myophathy, rhabdomyolysis, serious liver problems and kidney problems.
Therapies do exist to treat diabetes, such as α-glucosidase inhibitors, biguanides, thiazolidinediones, meglitinides, sulfonylureas and exogenous insulin. However, these therapies have limited effectiveness and are associated with significant safety and tolerability issues such as risk for hypoglycemic episodes, weight gain, gastrointestinal disturbances and anemia. In addition, many of the treatment options require injection or multiple daily dosing which present compliance challenges.
Thus, there exists a need for the identification of antilipolytic agents for the treatment of metabolic-related disorders such as dyslipidemia, atherosclerosis and diabetes. The present invention satisfies this need and provides related advantages as well.